Inhalation provides an effective means for delivering a variety of drugs, including nasal decongestants, drugs useful in the treatment of asthma and other bronchial and pulmonary conditions (1). One advantage of inhalation in treating nasal, bronchial, and pulmonary conditions is the ability to deliver the drug directly to the site of drug action. A related advantage is the rapid onset of the therapeutic effect, compared with other routes of administration, such as intramuscular and oral routes. For drugs which are susceptible to breakdown in the gastrointestinal tract, or which otherwise cannot be administered orally, inhalation may be preferred for a variety of reasons over intravenous or intramuscular injection. Other drugs, such as nitroglycerin, whose primary drug action is systemic, can also be delivered efficiently by inhalation.
Several methods for delivering drugs via inhalation are known. In one, the drug is dissolved in a suitable solvent which can be aerosolized to form a small-particle mist. The drug solution may be aerosolized by pneumatic or ultrasonic nebulizer, or, more conveniently, by means of a self-contained nebulizer containing a pressurized, fluorocarbon propellant. Inhalation of the aerosol mist, i.e., drawing the mist from the mouth or nose into the respiratory tract, acts to deposit the drug-containing aerosol particles on various sites of the respiratory tract, including the upper nasopharyngeal region, the tracheobronchial region, and the pulmonary region. In the latter region, the drug has the opportunity for rapid absorption into the bloodstream for systemic action.
Also well known in the prior art are inhalation systems in which a drug is administered in particulate form, either as a dry powder or as a micronized suspension in a suitable carrier solvent system. Typically the drug is a water-soluble compound which is suspended in micronized form in a fluorocarbon-type propellant solvent. Following aerosolization, most of the propellant solvent is lost through flash evaporation and replaced by moisture in the respiratory tract, leading to the deposition of hydrated micronized particles.
Both types of inhalation systems mentioned above are based on delivery of the drug in a free form to sites in the respiratory tract. As such, the drug is rapidly utilized and, in the case of pulmonary deposition, taken up systemically at the site of deposition. Because of this rapid drug uptake and utilization, the drug effect may be relatively short-lived, requiring frequent dosing. A related problem is the limited amount of drug that can be administered safely at each dosing, particularly where the drug has unwanted systemic side effects. This problem is illustrated by a number of .beta..sub.2 -adrenergic agonist type brochodilators which also produce marked tachycardia. Even at relatively low doses of these drugs, the stimulatory effect of the drug on the heart and other side effects, such as dizziness and insomnia, are a nuisance to the patient. Additionally, micronized particles may irritate the respiratory tract.
More recently, liposome inhalation systems for administering a drug to the respiratory tract in liposome-entrapped form have been proposed. UK patent application GB 2,145,107A describes an aerosol device which brings aqueous and organic-solvent phase solutions together under pressure, and passes the mixture through a nozzle to form aerosolized liposomes. EPO patent application 0,158,441 discloses liposome formation, in aerosol form, from a water/lipid/ethanol mixture. In PCT application WO 86/01714, it is proposed to spray lipid droplets in a volatile liquid carrier, with liposome formation occurring upon contact of the droplets with a moist aqueous surface. UK patent application GB 2,170,815 describes a system in which an aqueous solution is emulsified in a lipid-containing propellant solvent, then sprayed through an atomizing nozzle to form lipid-coated droplets which can form liposomes upon contact with a moist surface. All of these approaches are characterized by "in situ" liposome formation, i.e., liposome formation at the spray valve or on contact with the moist surface of the lungs. As such, the concentration and size of the liposomes formed, and the percentage of drug entrapment in the liposomes, will vary from one dose delivery to another, depending upon temperature and humidity conditions, the extent of solvent mixing, and the total and relative amounts of solvent components present in the system. Thus each of these systems would be difficult to adapt for metered dose delivery, in which a reproducible amount of liposome-encapsulated drug is needed.